Glial derived tumors or “gliomas” are transformed cells that display increased metabolic activity as a result of the transformation process. Gliomas comprise a diverse group of neoplasms that differ in their morphology, their CNS location, their degree of invasiveness, their tendency for progression, and their growth characteristics. Neoplastic transformation can occur in all glial types which allow the production of a large variety of pathological and morphological variants. Most primary brain tumors derived from glial cells have lost growth control regulation which gives rise to astrocytomas, glioblastomas, or oligodendrocytomas.
The most important determinant of survival for gliomas is the “grade” of the glioma. The low grade gliomas are easier to treat while the high grade gliomas (anaplastic astrocytoma and glioblastoma) are much more difficult to successfully treat. High grade gliomas account for about 30% of primary brain tumors in adults and are the second most common cause of cancer death in children under age 15. (The Children's Brain Tumor Foundation Internet Site; the American Brain Tumor Association Internet Site)
Gliomas have specific signs and symptoms that are primarily related to the location of the glioma. For example, gliomas found in the temporal lobe of the brain may cause epilepsy, difficulty with speech or loss of memory. Gliomas located in the frontal lobe may cause behavioral changes, weakness in the extremities, or difficulty with speech. Gliomas in the occipital lobe may cause loss of vision. Gliomas in the parietal lobe may cause loss of spatial orientation, diminished sensation on the opposite side of the body, or the inability to recognize once familiar objects or people.
The World Health Organization (WHO) has subdivided gliomas by histological grade. These grades are an indication of differentiation status, malignant potential, response to treatment, and survival. (Noushmehr, H. et al. 2010. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell. Vol. 17:510-522) Increasing grade indicates increasing malignancy and decreasing differentiation, which is associated with increased mitotic activity and enhanced cell migration. Grades are classified from Grade I through Grade IV.
Grade I gliomas are generally slow growing, exhibit few mitotic features and are characterized by most cells having normal characteristics. Grade II gliomas have an increased number of cells with polymorphic nuclei in mitosis and there is no clear line of demarcation from normal cells. High grade gliomas are divided by grade into two categories: anaplastic astrocytomas (Grade III) and glioblastoma multiforme (Grade IV). (Schoenberg, B. S. (1983) Epidemiology of central nervous system tumor. In: Walker, M. D., editor. Oncology of the Nervous System. Boston: Nijhoff; p. 1-30; Levin et al., (1989) Neoplasms of the central nervous system. In: Devita, S. et al. editors. Cancer: Principles and Practice of Oncology. 3rd edition, Philadelphia, Pa.: Lippincott; p. 1557-1611; Kleihues, P. et al., (1999) Primary and secondary glioblastomas: from concept to clinical diagnosis. Neuro-Oncol. 1:44-51)
Glioblastomas are Grade IV gliomas and are the most lethal primary brain tumor with a median survival of less than 12 months because of resistance to radiation and other treatments. (Bao, S. et al. 2006. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. Vol. 444:756-760) Most glioblastomas are diagnosed as de novo or primary tumors. These primary tumors exhibit cellular pleomorphism, vascular proliferation, mitoses, and multinucleated giant cells. Glioblastomas are more common in males than females. Approximately 5% of glioblastoma tumors are secondary tumors which progress from lower-grade tumors, such as grades II and III. These secondary tumors are usually seen in younger patients, are more evenly distributed between males and females, and exhibit longer survival times than primary tumors. (Noushmehr et al. 2010) Tumor cells of glioblastoma are the most undifferentiated among the brain tumors which allows the tumor cells to exhibit high potentials for migration and proliferation. Glioblastomas are highly invasive which contributes to the poor prognosis once onset occurs. Glioblastomas present as diffuse tumors with invasion into normal brain, but frequently recur or progress after radiation as focal masses, suggesting that only a fraction of tumor cells is responsible for regrowth. (Bao, S. et al. 2006)
The current method of diagnosing gliomas is through biopsy and evaluation of tissue histology. It would be highly desirable to have a biomarker for the detection of high grade gliomas. Furthermore, it would be highly desirable to have a screening methodology to evaluate the potential for successful therapy in subjects having high grade gliomas. Additionally, it would be highly desirable to have additional treatment regimens targeting the biochemical processes associated with high grade gliomas.
New prognostic and predictive markers are needed to accurately predict patient response to treatment, such as small molecule and biological molecule drugs. The classification of patient samples is crucial to cancer diagnosis and treatment. Associating a patient's response to treatment with molecular and genetic markers can elucidate new opportunities for treatment in non-responding patients or indicate one treatment over other treatment choices. By pre-selecting patients who are likely to respond well to an agent or combination therapy can reduce the number of patients needed in a clinical study or accelerate the time needed to complete a clinical development program (Cockett et al., Current Opinion in Biotechnology (2002) 11:602-609)
While it is known that the prognosis of high grade gliomas/glioblastoma multiform worsens with age, the basis for this observation is unknown. It is also common knowledge that cellular senescence and tumorigenesis are related and involve emergence of genomic instability, alterations of the telomere, emergence of autophagy, and alterations in mitochondrial metabolism and energy-dependent signal transduction. Thus what is needed is a diagnostic marker for classifying subjects according to the prediction of response to therapy for subjects having high grade glioma; diagnosis of high grade glioma; monitoring progression of high grade glioma from one biological state to another; and efficacy of treatment for high grade glioma.